Studies continue to show the important role of RVs as a cause of diarrheal illnesses of infants and young children. In the Global Enteric Multicenter Study (Kotloff et al, 2013) rotavirus was the most frequent cause (16.3-27.8%) of moderate-to-severe diarrhea in the 0-11 month old age group at each of 7 individual sites studied in The Gambia, Mali, Mozambique, Kenya, India, Bangladesh and Pakistan. In addition , Walker et al in 2013 estimated that worldwide in 2011 in children less than 5 years of age, 700,000 deaths were attributed to diarrheal illnesses and RVs were the most common cause, responsible for 192,700 deaths, predominantly in the developing regions. RVs have emerged as the single most important cause of severe diarrhea of infants and young children in both developed and developing countries in the under 5 yr age group, RVs are egalitarian as they infect infants and young children with similar frequency in countries with high or low socio-economic conditions but the consequences are very different. We developed an oral, live, attenuated quadrivalent RV vaccine to protect against the 4 epidemiologically important serotypes (G1-4).The vaccine was comprised of each of the following 4 serotypes: rhesus RV (RRV), a G3 strain, (the Jennerian approach), and 3 human RV-RRV reassortants, each possessing 10 RRV genes and a single human RV gene that encodes VP7 (a major outer shell protein) that is responsible for serotype G1, G2, or G4 specificity (the modified Jennerian approach). Following clinical studies which demonstrated the vaccine's safety, immunogenicity and efficacy especially against severe diarrheal disease, the ACIP, which advises the CDC, recommended its routine use for infants at 2, 4, and 6 months of age. In Aug 1998 the FDA granted a Biologics License for the vaccine (RotaShield RRV-TV) to Wyeth Labs. However, in July 1999, after over one million doses had been given to an estimated 600,000 infants, the CDC recommended suspending further vaccination because post-licensure surveillance suggested that the vaccine was linked with intussusception (IS). Following additional CDC studies, in Oct 1999 the ACIP withdrew its recommendation because of additional data which supported this link. In conjunction with these events, Wyeth Labs withdrew the vaccine. However, later analysis demonstrated that age of vaccination was a critical factor in the link with IS. In the CDC case-control study, vaccinees who were 90 days of age or older at the time of the first dose developed 81% of all cases occurring within 2 weeks of vaccination, even though they received only 38% of all first doses. Thus, catch-up vaccination of older infants during the age period of high vulnerability to IS (3 or 4 to 9 months of age) contributed disproportionately. There are questions regarding the vaccine's actual attributable risk of IS, a risk estimate that has ranged widely with a consensus figure of 1 in 10,000. Because the RRV-TV vaccine was associated with a transient and characteristically low grade fever in up to about one-third of vaccinees and the knowledge that bovine RV-based vaccines were characteristically non-reactogenic, in parallel with RRV-TV vaccine studies,we had initiated studies with individual human-bovine rotavirus (UK) reassortants and found that they were safe and immunogenic. These were followed by clinical studies of the 4 reassortants combined, a formulation that represented the 4 important RV serotypes, and showed that this vaccine (BRV-TV) was also safe and immunogenic. In a Wyeth-Univ. of Tampere-NIH collaborative clinical study in Finland, in which the RRV-TV and BRV-TV were evaluated in a two-dose schedule, the BRV-TV and RRV-TV each induced a high level of protection against severe RV diarrhea over two RV seasons. The BRV-TV vaccine did not induce a significantly greater number of febrile episodes after vaccination when compared to controls whereas RRV-TV did. In addition, another Wyeth-University of Tampere-NIH study in Finland evaluating the effect of administering RRV-TV vaccine or placebo in 3 different schedules, showed that neonates did not develop a febrile response after the neonatal dose. In addition, the neonatal dose induced significant protection against the development of a febrile response when infants received a second dose at 2 months of age. We have pursued our continued interest in RV vaccines especially for the developing countries where the toll from diarrheal diseases is immense. The NIH granted an exclusive license to BIOVIRx, Inc., a U.S. company (which was later transferred to the non-profit International Medica Foundation (IMF). This effort with RRV-TV stalled initially but was revived when funding became available from the IMF. Thus, a quadrivalent RRV-TV vaccine (RotaShield) was produced by The IDT Biologika GmbH in Germany, and became available in 2009 for clinical trial. A placebo-controlled phase II safety and efficacy trial began with RotaShield in Ghana on Aug. 28, 2009. By the end of Nov 2009 almost 1000 infants were given the 2nd dose of RotaShield or placebo: the 1st dose within the first 29 days of life and the 2nd dose before 60 days of age with a minimum interval of 3 weeks. The study period ended at the end of November, 2010 when the final participant reached an age within two weeks of the first birthday. In the intent-to-treat (ITT) and per-protocol (PP) analyses the vaccine demonstrated significant efficacy of 60.7% and 64.3%, respectively, against any RV diarrhea of any severity. Efficacy against severe RV diarrhea with any serotype was 53.5% (ITT) and 57.6% (PP) but these numbers were not significant. In a subset of individuals, the vaccine induced a 4-fold or greater IgA ELISA antibody response in 48% of vaccines and 0.8% of placebo recipients after dose 1 and in 56.7% of vaccinees and 3.4 % of placebo recipients after dose 2. Efforts to implement our 2nd generation vaccine, the human RV-bovine RV reassortant vaccine (BRV) for the developing countries have advanced. The NIH OTT initially granted licenses to develop the bovine RV-based vaccine to 8 institutions, 1 in the U.S. and 7 in developing countries (Brazil, China and India). Four of the 8 have engaged in vaccine production and in various stages of early clinical trials (one of these in India was suspended- contamination- but phase I/II study of G1-G4 vaccine now completed and phase III study planned in 2014 in 2014 ; another licensee has completed phase I/II studies in India and is planning a phase 3 trial of a pentavalent vaccine G1-4, G9) in approx. 7500 children to begin enrollment later this year supported by PATH via the Gates Foundation; and another licensee is producing a hexavalent vaccine (G1-4, G8, G9) with support from PATH via Gates Foundation and anticipates Phase 1 trials in late 2014. Another licensee in Brazil has developed a pentavalent (G1-4, G9) vaccine and carried out phase I/II studies in adults. Another licensee in China is developing a hexavalent vaccine (G1-4, G9, P1A) vaccine.. The manufacture of the vaccine in developing countries should result in its low cost. Our goal of vaccine implementation for the developing world has received an unsolicited boost, with the support to selected licensees by PATH via the Gates Foundation. A recent development has been the licensing to PATH for development via Gates Foundation) of an inactivated recombinant vaccine developed by Hoshino and his colleagues described as VP8 Recombinant P2-P8 delta VP8*(Wa) expressed in E coli . P2 is a universal T cell epitope of tetanus toxin. Phase I/II clinical studies have been carried out by PATH in adult volunteers. Also, another recombinant developed by Hoshino and his colleagues described as VP8 Recombinant P2-P8 delta VP8*(Wa)-P6 delta VP8* (1076) expressed in E.coli has been licensed to a lab in China.